Mice lacking the EGF receptor (EGFR) pass away between midgestation and postnatal day 20 with various defects in neural and epithelial organs. by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNF in the serum and prolonged activation of c-Jun. Moreover, p38 and NF-B activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is usually a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration. also displayed impaired hepatocyte proliferation and delayed induction of cyclin D1 after PH (19). However, it cannot be excluded that this high redundancy among the EGFR ligands might mask additional functions of the EGFR during liver regeneration. Therefore, definitive conclusions about the requirement of signaling during liver function and regeneration can be reached only after analyzing mice harboring liver-specific deletions of the allele (Allele. A targeting vector in which the promoter and the first exon of the gene are flanked by loxP sites was used to generate ES cells harboring a floxed allele (mice were fertile and phenotypically indistinguishable from control mice suggesting that the genetic manipulations and the presence of the neo cassette did not interfere with gene function (data not shown). After cre-mediated recombination of the allele the first exon and part of the promoter region are deleted giving rise to the and generates a null allele, we crossed mice with transgenic mice that express cre in all embryonic cells (24). (knockout mice (8, 10, 25) and Western blot analysis confirmed that no EGFR protein was expressed in mice. (locus with the restriction sites and DNA probe utilized for Southern blot analysis. The targeting construct for homologous recombination in ES cells harbors 850717-64-5 IC50 a neomycin (neo) resistance … Deletion of in the Liver. To analyze the function of EGFR during perinatal and early postnatal liver development, IFNA-J was inactivated 850717-64-5 IC50 tissue specifically in hepatocytes by using transgenic mice, in which the cre recombinase is usually under the control of the liver-specific albumin promoter and albumin and -feto-protein enhancers (26). (allele was already observed around P0 in the livers and deletion was almost total by P20 (Fig. 2livers revealed that EGFR protein was still detectable at low levels until P20 and total 850717-64-5 IC50 absence of the EGFR was only observed after 60 days (Fig. 2in the liver. (and mice at numerous times after birth. Results symbolize the imply SEM of six litters from five impartial breeding cages. *, < 0.05; **, < ... We further confirmed these results by employing a second impartial transgenic collection expressing cre under the control of the IFN--inducible Mx promoter, which is usually active in parenchymal and nonparenchymal liver cells as well as several other organs (27). Adult Mx-cre (and SI Fig. 8recombination at the genomic level, absence of the EGFR protein in the liver occurred only 3C4 weeks later similarly to what was observed in livers (SI Fig. 8protein still persists long after the allele is usually deleted. deletion in adult mice did not lead to growth retardation even when deletion was induced around day 9 after birth, the earliest time point at which pIpC injection did not lead to lethality (data not shown). mice did not develop any apparent phenotypical alterations or premature death up to 18 months after pIpC injection (data not shown). These results demonstrate that additional deletion of the in nonparenchymal liver cells does not lead to a more severe phenotype than what was observed in mice. Analysis of several parameters of liver function, including serum bilirubin, triglycerides, cholesterol, and aspartate aminotransferase/alanine aminotransferase did not reveal differences in and mice when compared with control littermates at 6 and 12 months of age (data not shown). Moreover, the liver-to-body excess weight ratio was comparable in and and their respective controls (SI Fig. 8mice, both and mice did not develop any indicators of impaired liver function. Liver Regeneration Is usually Impaired in the Absence of EGFR. To investigate whether EGFR is required during liver regeneration, two-thirds PH was performed on both and mice. Western blot analysis confirmed the absence of EGFR protein before and after PH in both and mice (SI Fig. 8in the liver (data not shown)..

Mice lacking the EGF receptor (EGFR) pass away between midgestation and
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